Clinical trials of R-(-)-gossypol (AT-101) in newly diagnosed and recurrent glioblastoma: NABTT 0602 and NABTT 0702.

PURPOSE: AT-101 is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of the parent compound, racemic gossypol, demonstrated objective and durable responses in patients with malignant glioma. AT-101 has demonstrated synergy with radiation in animal models. The objectives of trial NABTT 0602 were to determine the MTD of AT-101 concurrent with temozolomide (TMZ) and radiation therapy (RT) (Arm I) and to determine the MTD of AT-101 when given with adjuvant TMZ after completion of standard chemoradiation (Arm 2). Separately in trial NABTT 0702, the survival and response rates of single agent AT-101 were evaluated in patients with recurrent glioblastoma. METHODS: In NABTT 0602 Phase I, a 3+3 design was used to define MTDs after maximal safe resection, patients with newly diagnosed glioblastoma received standard concurrent RT (60 Gy) and TMZ 75 mg/m2/day followed by adjuvant TMZ 150-200 mg/m2 days 1-5 in 28-day cycles (Stupp regimen). In Arm I, AT-101 was administered M-F during the six weeks of RT beginning 20 mg qd. In Arm 2, concurrent with each adjuvant cycle of TMZ, AT-101 was administered at a starting dose of 20 mg, days 1-21 followed by 7-day break for a maximum of 6 cycles. The PK blood samples were collected in the first three patients in each cohort of arm 1. In NABTT 0702 patients with recurrent glioblastoma received 20 mg p.o. per day for 21 of 28 days in repeated cycles to assess overall survival (OS). RESULTS: A total of sixteen patients were enrolled on the two study arms of NABTT 0602. In Arm 1 AT-101 was escalated from 20 to 30 mg where one of six patients experienced DLT (grade 3 GI ulcer). On Arm 2 one patient treated at 20 mg experienced DLT (grade 3 ileus, nausea and diarrhea). The cohort was expanded to include seven patients without observation of DLT. PK results were consistent with drug levels from non-CNS studies. At study closure six patients are still alive. The median survival times for Arm I and Arm II are 15.2 months and 18.2 months, respectively. In NABTT 0702 fifty-six patients were enrolled and forty-three were eligible for imaging response. Sixteen patients (29%) had stable disease as best response and one partial response was observed. The median OS with single agent AT-101 was 5.7 months (95%CI: 3.8-7.6 months) for patients with rGBM. CONCLUSIONS: AT-101 can be safely administered with radiation therapy and TMZ in patients with newly diagnosed glioblastoma without toxicity unique to patients with CNS tumors. Because of toxicity observed in non-CNS AT-101 clinical trials, further dose-escalation was not attempted. The recommended dose for future studies that utilize continual AT-101 exposure is 20 mg days M-F concurrent with RT/TMZ and 20 mg days 1-21 for each 28-day cycle of TMZ. AT-101 has limited activity as a single agent in unselected patients with recurrent glioblastoma. Future trials should attempt to better understand resistance mechanisms and consider combination therapy.

Human CASPR2 Antibodies Reversibly Alter Memory and the CASPR2 Protein Complex.

OBJECTIVE: The encephalitis associated with antibodies against contactin-associated proteinlike 2 (CASPR2) is presumably antibody-mediated, but the antibody effects and whether they cause behavioral alterations are not well known. Here, we used a mouse model of patients' immunoglobulin G (IgG) transfer and super-resolution microscopy to demonstrate the antibody pathogenicity. METHODS: IgG from patients with anti-CASPR2 encephalitis or healthy controls was infused into the cerebroventricular system of mice. The levels and colocalization of CASPR2 with transient axonal glycoprotein 1 (TAG1) were determined with stimulated emission depletion microscopy (40-70µm lateral resolution). Hippocampal clusters of Kv1.1 voltage-gated potassium channels (VGKCs) and GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) were quantified with confocal microscopy. Behavioral alterations were assessed with standard behavioral paradigms. Cultured neurons were used to determine the levels of intracellular CASPR2 and TAG1 after exposure to patients' IgG. RESULTS: Infusion of patients' IgG, but not controls' IgG, caused memory impairment along with hippocampal reduction of surface CASPR2 clusters and decreased CASPR2/TAG1 colocalization. In cultured neurons, patients' IgG led to an increase of intracellular CASPR2 without affecting TAG1, suggesting selective CASPR2 internalization. Additionally, mice infused with patients' IgG showed decreased levels of Kv1.1 and GluA1 (two CASPR2-regulated proteins). All these alterations and the memory deficit reverted to normal after removing patients' IgG. INTERPRETATION: IgG from patients with anti-CASPR2 encephalitis causes reversible memory impairment, inhibits the interaction of CASPR2/TAG1, and decreases the levels of CASPR2 and related proteins (VGKC, AMPAR). These findings fulfill the postulates of antibody-mediated disease and provide a biological basis for antibody-removing treatment approaches. ANN NEUROL 2022;91:801-813.

Clinical features, prognostic factors, and antibody effects in anti-mGluR1 encephalitis.

OBJECTIVE: To clinically characterize patients with anti-metabotropic glutamate receptor (mGluR) 1 encephalitis, to identify prognostic factors, and to study the immunoglobulin G (IgG) subclasses and effects of antibodies on neuronal mGluR1 clusters. METHODS: Clinical information on new and previously reported patients was reviewed. Antibodies to mGluR1 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays, and their effects on mGluR1 clusters were studied on rat hippocampal neurons. RESULTS: Eleven new patients were identified (10 adults, 1 child);4 were female. In these and 19 previously reported cases (n = 30, median age 55 years), the main clinical manifestation was a subacute cerebellar syndrome that in 25 (86%) patients was associated with behavioral/cognitive changes or other neurologic symptoms. A tumor was found in 3 of 26 (11%). Brain MRI was abnormal in 7 of 19 (37%) at onset and showed cerebellar atrophy in 10 of 12 (83%) at follow-up. Twenty-five of 30 (83%) patients received immunotherapy. Follow-up was available for 25: 13 (52%) had clinical stabilization; 10 (40%) showed significant improvement; and 2 died. At the peak of the disease, patients with bad outcome at 2 years (modified Rankin Scale score > 2, n = 7) were more likely to have higher degree of initial disability, as reflected by a worse Scale for Assessment and Rating of Ataxia score, and more frequent need of assistance to walk. Antibodies to mGluR1 were mainly IgG1 and caused a significant decrease of mGluR1 clusters in cultured neurons. CONCLUSIONS: Anti-mGluR1 encephalitis manifests as a severe cerebellar syndrome, often resulting in long-term disability and cerebellar atrophy. The antibodies are pathogenic and cause significant decrease of mGluR1 clusters in cultured neurons.

An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models.

The identification of anti-NMDA receptor (NMDAR) encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.

Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM). PATIENTS AND METHODS: Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi- institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy + temozolomide + iniparib (n = 5) was followed by an efficacy study (n = 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy + daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide). RESULTS: The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥ 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17-24] and the HR was 0.44 (95% CI, 0.35-0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. CONCLUSIONS: Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

Paraneoplastic Neurologic Syndromes.

Paraneoplastic neurologic syndromes (PNS) are mostly immune-mediated disorders that occur in patients with cancer. Because the same neurologic syndromes may occur without a cancer association it is important to know the likelihood of PNS, which is based in part on the syndrome and the patient's demographics and risk factors for cancer. The presence of specific antineuronal antibodies can facilitate the diagnosis and suggest treatment strategies. Although some PNS are rarely responsive to therapies, other disorders are highly treatment responsive.

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.

BACKGROUND: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. METHODS: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. FINDINGS: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). INTERPRETATION: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy. FUNDING: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.

Encephalitis with mGluR5 antibodies: Symptoms and antibody effects.

OBJECTIVE: To report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters. METHODS: Clinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques. RESULTS: From January 2005 to May 2017, 11 patients (median age 29 years, range 6-75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm3) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunotherapy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients' IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95. CONCLUSIONS: Anti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5.

Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor.

OBJECTIVE: To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM N-methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis. METHODS: Evaluation of IgG, IgA, and IgM NMDAR antibodies in serum of 300 patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining. Retrospective analysis of the clinical diagnoses of a cohort of 1,147 patients with IgG NMDAR antibodies identified since 2005. RESULTS: Among the 300 patients studied, IgG NMDAR antibodies were only identified in those with anti-NMDAR encephalitis and all reacted with brain and live neurons. By cell-based assay, IgA or IgM antibodies were detected in 22 of 300 patients (7%) with different diseases, but only 10 (3%) reacted with brain and 7 (2%) with live neurons. In cultured neurons, IgG but not IgA or IgM antibodies caused a decrease of synaptic and extrasynaptic NMDAR. Among the cohort of 1,147 patients with IgG NMDAR antibodies, 1,015 (88.5%) had anti-NMDAR encephalitis, 45 (3.9%) a limited form of the disease, 41 (3.6%) autoimmune post-herpes simplex encephalitis, 37 (3.2%) overlapping syndromes (anti-NMDAR encephalitis and demyelinating disease), and 9 (0.8%) atypical encephalitic syndromes; none had schizophrenia. CONCLUSIONS: IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.

Procarbazine, lomustine and vincristine for recurrent high-grade glioma.

BACKGROUND: Recurrent high-grade glioma (HGG) carries an extremely poor prognosis. There is no current standard of care or guideline-based recommendations. Nitrosourea-based multidrug chemotherapy or PCV - procarbazine, lomustine (CCNU) and vincristine - is one of the treatment options at recurrence. There has been no meta-analysis which looks at the benefits and harms of PCV chemotherapy in adults with recurrent HGG. OBJECTIVES: To assess the effectiveness and safety of procarbazine, lomustine, and vincristine (PCV) chemotherapy with other interventions in adults with recurrent high-grade glioma. To investigate whether predefined subgroups of people benefit more or less from chemotherapy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2017), MEDLINE (1946 to 22 May 2017), and Embase (1980 to 22 May 2017). We searched trial registries including the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch) and the National Institutes of Health (NIH; ClinicalTrials.gov). We searched the reference lists of all identified studies; the electronic table of contents of the Journal of Neuro-Oncology (1983 to 2016) and Neuro-Oncology (1999 to 2016); and conference abstracts from the Society for Neuro-Oncology (SNO) and the American Society of Clinical Oncology (ASCO 2004 to 2016). We also searched unpublished grey literature and other regional databases. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-randomised trials (QRCTs), or controlled clinical trials (CCTs) where PCV was used to treat adults with recurrent HGG. Comparison arm included no chemotherapy, other second line chemotherapy or best supportive care. DATA COLLECTION AND ANALYSIS: Two review authors extracted the data and undertook a 'Risk of bias' assessment and critical appraisal of the studies. MAIN RESULTS: We identified two RCTs meeting our inclusion criteria. The two trials tested different comparisons.One RCT included 35 participants and compared PCV with 'eight drugs in one day' multidrug chemotherapy, which is a combination of drugs with different mechanisms of action. Median survival was 6 months for the PCV group and 6.5 months for the 'eight drugs in one day' group. Adverse event outcomes were not graded or quantified. Progression-free survival (PFS) and quality of life (QoL) were not described in the methods and were not an outcome of interest. The sample size in this study was small, which lead to insufficient statistical power to detect clinical differences. According to the GRADE approach we judged the quality of evidence to be low for survival outcome and very low for chemotherapy toxicityThe second multi-institutional RCT included 447 participants and compared PCV with Temozolomide (TMZ). Participants were randomised into three arms to receive PCV, and two different regimens of TMZ in a 2:1:1 ratio at first recurrence. The trial reported a median overall survival of 6.7 months and 7.2 months for the PCV and TMZ group respectively. It reported a PFS of 3.6 months for the PCV group and 4.7 months for the TMZ group. There was no observed difference of effect on overall survival (hazard ratio (HR) 0.91, 95% CI 0.74 to 1.11; P = 0.35) or PFS (HR 0.89, 95% CI 0.73 to 1.08; P = 0.23) in participants receiving PCV or TMZ chemotherapy. The proportion of people with at least one grade 3 or 4 adverse event was not clinically important at 9.2% versus 12.2% in PCV and TMZ arms respectively. Mean QoL scores calculated at baseline, 12 weeks and 24 weeks was 51.9 versus 59.8 favouring TMZ (P = 0.04) which is statistically but not clinically significant and was less than the pre-defined 10 point change for moderate improvement. We judged the GRADE quality of evidence to be moderate for overall survival, PFS, and chemotherapy toxicity and low for QoL. AUTHORS' CONCLUSIONS: Evidence is based on a single large trial analysis as the other trial was small, with inadequate power to detect survival difference. Chemotherapy-naive patients with HGG at first recurrence when treated with PCV or TMZ have similar survival and time-to-progression outcomes. Adverse events are similar and QoL scores are statistically but not clinically significant between TMZ and PCV. Further RCTs should be conducted with adequate power following CONSORT guidelines with emphasis on QoL outcomes.

DPPX antibody-associated encephalitis: Main syndrome and antibody effects.

OBJECTIVE: To report the main syndrome of dipeptidyl-peptidase-like protein 6 (DPPX) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and the antibody effects on DPPX/Kv4.2 potassium channels. METHODS: A retrospective analysis of new patients and cases reported since 2013 was performed. IgG subclass and effects of antibodies on cultured neurons were determined with described techniques. RESULTS: Nine new patients were identified (median age 57 years, range 36-69 years). All developed severe prodromal weight loss or diarrhea followed by cognitive dysfunction (9), memory deficits (5), CNS hyperexcitability (8; hyperekplexia, myoclonus, tremor, or seizures), or brainstem or cerebellar dysfunction (7). The peak of the disease was reached 8 months (range 1-54 months) after onset. All patients had both IgG4 and IgG1 DPPX antibodies. In cultured neurons, the antibodies caused a decrease of DPPX clusters and Kv4.2 protein that was reversible on removal of the antibodies. Considering the current series and previously reported cases (total 39), 67% developed the triad: weight loss (median 20 kg; range 8-53 kg)/gastrointestinal symptoms, cognitive-mental dysfunction, and CNS hyperexcitability. Outcome was available from 35 patients (8 not treated with immunotherapy): 60% had substantial or moderate improvement, 23% had no improvement (most of them not treated), and 17% died. Relapses occurred in 8 of 35 patients (23%) and were responsive to immunotherapy. CONCLUSIONS: DPPX antibodies are predominantly IgG1 and IgG4 and associate with cognitive-mental deficits and symptoms of CNS hyperexcitability that are usually preceded by diarrhea, other gastrointestinal symptoms, and weight loss. The disorder is responsive to immunotherapy, and this is supported by the reversibility of the antibody effects in cultured neurons.

Investigations in GABAA receptor antibody-associated encephalitis.

OBJECTIVE: To report the clinical features, comorbidities, receptor subunit targets, and outcome in patients with anti-GABAA receptor (GABAAR) encephalitis. METHODS: Clinical study of 26 patients, including 17 new (April 2013-January 2016) and 9 previously reported patients. Antibodies to α1, ß3, and γ2 subunits of the GABAAR were determined using reported techniques. RESULTS: Patients' median age was 40.5 years (interquartile range 48.5 [13.75-62.35] years; the youngest 2.5 months old; 13 female). Symptoms included seizures (88%), alteration of cognition (67%), behavior (46%), consciousness (42%), or abnormal movements (35%). Comorbidities were identified in 11 (42%) patients, including 7 tumors (mostly thymomas), 2 herpesvirus encephalitis (herpes simplex virus 1, human herpesvirus 6; coexisting with NMDAR antibodies), and 2 myasthenia without thymoma. Brain MRI was abnormal in 23 (88%) patients, showing in 20 (77%) multifocal, asynchronous, cortical-subcortical T2/fluid-attenuated inversion recovery abnormalities predominantly involving temporal (95%) and frontal (65%) lobes, but also basal ganglia and other regions. Immunologic or tumor therapy resulted in substantial improvement in 18/21 (86%) assessable patients; the other 3 (14%) died (2 status epilepticus, 1 sepsis). Compared with adults, children were more likely to have generalized seizures (p = 0.007) and movement disorders (p = 0.01) and less likely to have a tumor (p = 0.01). The main epitope targets were in the α1/ß3 subunits of the GABAAR. CONCLUSIONS: Anti-GABAAR encephalitis is characterized by frequent seizures and distinctive multifocal cortical-subcortical MRI abnormalities that provide an important clue to the diagnosis. The frequency of symptoms and comorbidities differ between children (more viral-related) and adults (more tumor-related). The disorder is severe but most patients respond to treatment.

A clinical approach to diagnosis of autoimmune encephalitis.

Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.

Autoimmune post-herpes simplex encephalitis of adults and teenagers.

OBJECTIVE: To report 14 patients with immune-mediated relapsing symptoms post-herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children. METHODS: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously. RESULTS: Among the teenage and adult group (8 patients, median age 40 years, range 13-69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6-20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17-296, vs 4 days, range 0-33, p = 0.037). CONCLUSION: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.

Update on neurological paraneoplastic syndromes.

PURPOSE OF REVIEW: To provide an update on paraneoplastic neurologic syndromes (PNS), the involved tumors, and types of immune responses. RECENT FINDINGS: PNS are a diverse group of syndromes that may present as a relatively isolated syndrome such as predominant cerebellar degeneration or limbic encephalitis, or with more complex phenotypes such as diffuse encephalomyelitis that affects different levels of the neuraxis producing a variety of clinical manifestations. The detection of specific antineuronal antibodies can confirm or strongly support the paraneoplastic cause of the syndrome and direct the search for the associated cancer. Previously thought to be unresponsive to therapy, it has recently been shown that there are some antibody-associated PNS that are highly responsive to treatment, including tumor-directed therapies and immunotherapy. SUMMARY: The recognition of PNS is important for the early detection of an underlying malignancy and prompt initiation of therapies, which offers the best opportunity to stabilize or improve the neurological deficits and for those syndromes associated with cell surface antibodies usually results in substantial improvement or full recovery.

Phase I study of iniparib concurrent with monthly or continuous temozolomide dosing schedules in patients with newly diagnosed malignant gliomas.

Iniparib is a prodrug that converts to highly reactive cytotoxic metabolites intracellularly with activity in preclinical glioma models. We investigated the maximum tolerated dose (MTD) of iniparib with monthly (m) and continuous (c) temozolomide (TMZ) dosing schedules in patients with malignant gliomas (MG). Adults with newly diagnosed MG who had successfully completed ≥80% of radiation (RT) and TMZ without toxicity received mTMZ dosing (150-200 mg/m(2) days 1-5/28 days) or cTMZ dosing (75 mg/m(2)/days × 6 weeks) in conjunction with iniparib (i.v. 2 days/week) in the adjuvant setting. Iniparib was dose escalated using a modified continual reassessment method (mCRM). 43 patients (32 male; 34 GBM, 8 AA, 1 gliosarcoma; median age 54 years; median KPS 90) were enrolled across 4 dose levels. In the mTMZ group, 2/4 patients had dose limiting toxicities (DLT) at 19 mg/kg/week (rash/hypersensitivity). At 17.2 mg/kg/week, 1/9 patients had a DLT (grade 3 fatigue). Additional grade 3 toxicities were neutropenia, lymphopenia, and nausea. In the cTMZ group, one DLT (thromboembolic event) occurred at 10.2 mg/kg/week. Dose escalation stopped at 16 mg/kg/week based on mCRM. The mean maximum plasma concentration of iniparib increased with dose. Concentration of the two major circulating metabolites, 4-iodo-3-aminobenzamide and 4-iodo-3-aminobenzoic acid, was ≤5% of the corresponding iniparib concentration. Iniparib is well tolerated, at doses higher than previously investigated, in combination with TMZ after completion of RT + TMZ in patients with MG. Recommended phase 2 dosing of iniparib based on mCRM is 17.2 mg/kg/week with mTMZ and 16 mg/kg/week with cTMZ. An efficacy study of TMZ/RT + iniparib followed by TMZ + iniparib in newly diagnosed GBM using these doses has completed enrollment. Survival assessment is ongoing.

Brain Tumor Epidemiology - A Hub within Multidisciplinary Neuro-oncology. Report on the 15th Brain Tumor Epidemiology Consortium (BTEC) Annual Meeting, Vienna, 2014.

The Brain Tumor Epidemiology Consortium (BTEC) is an open scientific forum, which fosters the development of multi-center, international and inter-disciplinary collaborations. BTEC aims to develop a better understanding of the etiology, outcomes, and prevention of brain tumors (http://epi.grants.cancer.gov/btec/). The 15th annual Brain Tumor Epidemiology Consortium Meeting, hosted by the Austrian Societies of Neuropathology and Neuro-oncology, was held on September 9 - 11, 2014 in Vienna, Austria. The meeting focused on the central role of brain tumor epidemiology within multidisciplinary neuro-oncology. Knowledge of disease incidence, outcomes, as well as risk factors is fundamental to all fields involved in research and treatment of patients with brain tumors; thus, epidemiology constitutes an important link between disciplines, indeed the very hub. This was reflected by the scientific program, which included various sessions linking brain tumor epidemiology with clinical neuro-oncology, tissue-based research, and cancer registration. Renowned experts from Europe and the United States contributed their personal perspectives stimulating further group discussions. Several concrete action plans evolved for the group to move forward until next year's meeting, which will be held at the Mayo Clinic at Rochester, MN, USA.

Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response.

IMPORTANCE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable autoimmune encephalitis affecting mainly young adults and children. The lack of suitable biomarkers of disease activity makes treatment decisions and identification of relapses challenging. OBJECTIVE: To determine the levels of the B-cell-attracting C-X-C motif chemokine 13 (CXCL13) in serum samples and cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and whether they can be used as biomarkers of treatment response and outcome. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective cohort study of 167 patients consecutively diagnosed as having anti-NMDAR encephalitis between May 1, 2008, and January 31, 2013. Concentration of CXCL13 was determined with enzyme-linked immunosorbent assay in all available patients' samples (272 CSF and 55 serum samples). Samples from 25 patients with noninflammatory neurological disorders and 9 with neuroborreliosis served as controls. Expression of CXCL13 in the brain biopsy of a patient with anti-NMDAR encephalitis was determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES: Percentage of patients with anti-NMDAR encephalitis and elevated CXCL13 in CSF. RESULTS: Compared with control individuals, 70% of patients with early-stage anti-NMDAR encephalitis had increased CXCL13 in CSF (>7 pg/mL; P < .001) but none in serum samples (>1047 pg/mL; P > .99). High concentration of CSF CXCL13 was associated with the presence of prodromal fever or headache (P = .01), limited response to therapy (P = .003), clinical relapses (P = .03), and intrathecal NMDAR-antibody synthesis (P < .001). Among patients with monophasic disease assessed 2 to 6 months after starting treatment, 10 of 15 with limited treatment response vs 0 of 13 with favorable response had increased CSF CXCL13 (specificity, 100%; 95% CI, 75-100 and sensitivity, 67%; 95% CI, 38-88; P = .02). Six of 12 patients had elevated CSF CXCL13 at relapse including 3 with previously normal levels. In brain, abundant mononuclear cells in perivascular infiltrates and scattered intraparenchymal microglia expressed CXCL13. CONCLUSIONS AND RELEVANCE: Seventy percent of patients with early-stage anti-NMDAR encephalitis had increased CSF CXCL13 concentration that correlated with intrathecal NMDAR-antibody synthesis. Prolonged or secondary elevation of CXCL13 was associated with limited response to treatment and relapses. CXCL13 is a potentially useful biomarker of treatment response and outcome in anti-NMDAR encephalitis.